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ISSN (Online): 1875-5607

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Review Article

Triple Negative Breast Cancer: How Neurokinin-1 Receptor Antagonists Could Be Used as a New Therapeutic Approach

Author(s): Miguel Muñoz*, Marisa Rosso and Rafael Coveñas

Volume 20, Issue 5, 2020

Page: [408 - 417] Pages: 10

DOI: 10.2174/1389557519666191112152642

Price: $65

Abstract

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females. BC cells not showing HER-2/Neu amplification and not expressing estrogen/ progesterone receptors are named triple-negative BC (TNBC) cells. TNBC represents 10-15% of all BC and is associated with an aggressive clinical course. TNBC patient prognosis, survival and response to current therapies are poor and for this reason, it is crucial to search for new therapeutic targets in TNBC to develop new therapeutic strategies. One of these targets is the neurokinin-1 receptor (NK-1R). It is well known that the substance P (SP)/NK-1R system is involved in cancer progression. TNBC cells overexpress the NK-1R and, after binding to this receptor, SP promotes the proliferation/ migration of TNBC cells. Non-peptide NK-1R antagonists (e.g., aprepitant) are known to exert, via the NK-1R, an antitumor action; TNBC cells die by apoptosis. In this review, we update the data on a promising therapeutic innovation: the use of NK-1R antagonists for the treatment of TNBC patients.

Keywords: Substance P, NK-1 receptor, TNBC, aprepitant, antitumor, apoptosis, metastasis, angiogenesis.

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[1]
García, M.; Jemal, A.; Ward, E.M.; Center, M.M.; Hao, Y.; Siegel, R.L.; Thun, M.J. Global cancer facts & figures 2007; American Cancer Society, 2007.
[2]
Brenton, J.D.; Carey, L.A.; Ahmed, A.A.; Caldas, C. Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J. Clin. Oncol., 2005, 23(29), 7350-7360.
[http://dx.doi.org/10.1200/JCO.2005.03.3845] [PMID: 16145060]
[3]
Anders, C.K.; Carey, L.A. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin. Breast Cancer, 2009, 9(Suppl. 2), S73-S81.
[http://dx.doi.org/10.3816/CBC.2009.s.008] [PMID: 19596646]
[4]
Ilie, S.M.; Bacinschi, X.E.; Botnariuc, I.; Anghel, R.M. Potential clinically useful prognostic biomarkers in triple-negative breast cancer: Preliminary results of a retrospective analysis. Breast Cancer (Dove Med. Press), 2018, 10, 177-194.
[http://dx.doi.org/10.2147/BCTT.S175556] [PMID: 30538542]
[5]
Kaplan, H.G.; Malmgren, J.A.; Atwood, M. T1N0 triple negative breast cancer: Risk of recurrence and adjuvant chemotherapy. Breast J., 2009, 15(5), 454-460.
[http://dx.doi.org/10.1111/j.1524-4741.2009.00789.x] [PMID: 19671105]
[6]
Singh, D.; Joshi, D.D.; Hameed, M.; Qian, J.; Gascón, P.; Maloof, P.B.; Mosenthal, A.; Rameshwar, P. Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc. Natl. Acad. Sci. USA, 2000, 97(1), 388-393.
[http://dx.doi.org/10.1073/pnas.97.1.388] [PMID: 10618428]
[7]
Bigioni, M.; Benzo, A.; Irrissuto, C.; Maggi, C.A.; Goso, C. Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231. Anticancer Drugs, 2005, 16(10), 1083-1089.
[http://dx.doi.org/10.1097/00001813-200511000-00007] [PMID: 16222150]
[8]
Muñoz, M.; González-Ortega, A.; Salinas-Martín, M.V.; Carranza, A.; García-Recio, S.; Almendro, V.; Coveñas, R. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int. J. Oncol., 2014, 45(4), 1658-1672.
[http://dx.doi.org/10.3892/ijo.2014.2565] [PMID: 25175857]
[9]
Rodríguez, P.L.; Jiang, S.; Fu, Y.; Avraham, S.; Avraham, H.K. The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. Int. J. Cancer, 2014, 134(5), 1034-1044.
[http://dx.doi.org/10.1002/ijc.28433] [PMID: 23934616]
[10]
Davoodian, M.; Boroumand, N.; Mehrabi Bahar, M.; Jafarian, A.H.; Asadi, M.; Hashemy, S.I. Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in breast cancer. Mol. Biol. Rep., 2019, 46(1), 1285-1293.
[http://dx.doi.org/10.1007/s11033-019-04599-9] [PMID: 30684188]
[11]
Ziche, M.; Morbidelli, L.; Pacini, M.; Geppetti, P.; Alessandri, G.; Maggi, C.A. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc. Res., 1990, 40(2), 264-278.
[http://dx.doi.org/10.1016/0026-2862(90)90024-L] [PMID: 1701206]
[12]
Wang, J.G.; Yu, J.; Hu, J.L.; Yang, W.L.; Ren, H.; Ding, D.; Zhang, L.; Liu, X.P. Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer. Cell. Signal., 2015, 27(7), 1315-1324.
[http://dx.doi.org/10.1016/j.cellsig.2015.03.015] [PMID: 25817575]
[13]
Pennefather, J.N.; Lecci, A.; Candenas, M.L.; Patak, E.; Pinto, F.M.; Maggi, C.A. Tachykinins and tachykinin receptors: A growing family. Life Sci., 2004, 74(12), 1445-1463.
[http://dx.doi.org/10.1016/j.lfs.2003.09.039] [PMID: 14729395]
[14]
Takeda, Y.; Chou, K.B.; Takeda, J.; Sachais, B.S.; Krause, J.E. Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem. Biophys. Res. Commun., 1991, 179(3), 1232-1240.
[http://dx.doi.org/10.1016/0006-291X(91)91704-G] [PMID: 1718267]
[15]
Fong, T.M.; Anderson, S.A.; Yu, H.; Huang, R.R.; Strader, C.D. Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Mol. Pharmacol., 1992, 41(1), 24-30.
[PMID: 1310144]
[16]
Zhou, Y.; Zhao, L.; Xiong, T.; Chen, X.; Zhang, Y.; Yu, M.; Yang, J.; Yao, Z. Roles of full-length and truncated neurokinin-1 receptors on tumor progression and distant metastasis in human breast cancer. Breast Cancer Res. Treat., 2013, 140(1), 49-61.
[http://dx.doi.org/10.1007/s10549-013-2599-6] [PMID: 23807418]
[17]
Berger, M.; Neth, O.; Ilmer, M.; Garnier, A.; Salinas-Martín, M.V.; de Agustín Asencio, J.C.; von Schweinitz, D.; Kappler, R.; Muñoz, M. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo. J. Hepatol., 2014, 60(5), 985-994.
[http://dx.doi.org/10.1016/j.jhep.2013.12.024] [PMID: 24412605]
[18]
Muñoz, M.; Coveñas, R. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides, 2013, 48, 1-9.
[http://dx.doi.org/10.1016/j.peptides.2013.07.024] [PMID: 23933301]
[19]
Mitsuhashi, M.; Ohashi, Y.; Shichijo, S.; Christian, C.; Sudduth-Klinger, J.; Harrowe, G.; Payan, D.G. Multiple intracellular signaling pathways of the neuropeptide substance P receptor. J. Neurosci. Res., 1992, 32(3), 437-443.
[http://dx.doi.org/10.1002/jnr.490320315] [PMID: 1279191]
[20]
Nakajima, Y.; Tsuchida, K.; Negishi, M.; Ito, S.; Nakanishi, S. Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells. J. Biol. Chem., 1992, 267(4), 2437-2442.
[PMID: 1370820]
[21]
Takeda, Y.; Blount, P.; Sachais, B.S.; Hershey, A.D.; Raddatz, R.; Krause, J.E. Ligand binding kinetics of substance P and neurokinin A receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1,4,5-trisphosphate and cyclic AMP second messenger responses. J. Neurochem., 1992, 59(2), 740-745.
[http://dx.doi.org/10.1111/j.1471-4159.1992.tb09430.x] [PMID: 1321234]
[22]
Akazawa, T.; Kwatra, S.G.; Goldsmith, L.E.; Richardson, M.D.; Cox, E.A.; Sampson, J.H.; Kwatra, M.M. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J. Neurochem., 2009, 109(4), 1079-1086.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06032.x] [PMID: 19519779]
[23]
Geffken, K.; Spiegel, S. Sphingosine kinase 1 in breast cancer. Adv. Biol. Regul., 2018, 67, 59-65.
[http://dx.doi.org/10.1016/j.jbior.2017.10.005] [PMID: 29055687]
[24]
Pyne, N.J.; El Buri, A.; Adams, D.R.; Pyne, S. Sphingosine 1-phosphate and cancer. Adv. Biol. Regul., 2018, 68, 97-106.
[http://dx.doi.org/10.1016/j.jbior.2017.09.006] [PMID: 28942351]
[25]
Gillespie, E.; Leeman, S.E.; Watts, L.A.; Coukos, J.A.; O’Brien, M.J.; Cerda, S.R.; Farraye, F.A.; Stucchi, A.F.; Becker, J.M. Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer. Proc. Natl. Acad. Sci. USA, 2011, 108(42), 17420-17425.
[http://dx.doi.org/10.1073/pnas.1114275108] [PMID: 21969570]
[26]
Lang, K.; Drell, T.L., IV; Lindecke, A.; Niggemann, B.; Kaltschmidt, C.; Zaenker, K.S.; Entschladen, F. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int. J. Cancer, 2004, 112(2), 231-238.
[http://dx.doi.org/10.1002/ijc.20410] [PMID: 15352035]
[27]
Gutierrez, S.; Boada, M.D. Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+). Cancer Cell Int., 2018, 18, 216.
[http://dx.doi.org/10.1186/s12935-018-0707-8] [PMID: 30598641]
[28]
Meshki, J.; Douglas, S.D.; Lai, J.P.; Schwartz, L.; Kilpatrick, L.E.; Tuluc, F. Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism. J. Biol. Chem., 2009, 284(14), 9280-9289.
[http://dx.doi.org/10.1074/jbc.M808825200] [PMID: 19179340]
[29]
Meshki, J.; Douglas, S.D.; Hu, M.; Leeman, S.E.; Tuluc, F. Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner. PLoS One, 2011, 6(9) e25332
[http://dx.doi.org/10.1371/journal.pone.0025332] [PMID: 21966499]
[30]
Li, J.; Zeng, Q.; Zhang, Y.; Li, X.; Hu, H.; Miao, X.; Yang, W.; Zhang, W.; Song, X.; Mou, L.; Wang, R. Neurokinin-1 receptor mediated breast cancer cell migration by increased expression of MMP-2 and MMP-14. Eur. J. Cell Biol., 2016, 95(10), 368-377.
[http://dx.doi.org/10.1016/j.ejcb.2016.07.005] [PMID: 27498853]
[31]
Muñoz, M.; Coveñas, R.; Esteban, F.; Redondo, M. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs. J. Biosci., 2015, 40(2), 441-463.
[http://dx.doi.org/10.1007/s12038-015-9530-8] [PMID: 25963269]
[32]
Hökfelt, T.; Pernow, B.; Wahren, J.; Substance, P. A pioneer amongst neuropeptides. J. Intern. Med., 2001, 249(1), 27-40.
[http://dx.doi.org/10.1046/j.0954-6820.2000.00773.x] [PMID: 11168782]
[33]
Muñoz, M.; Parrilla, J.; Rosso, M.; Coveñas, R. Antipruritic vs. Antitumour action of aprepitant: A question of dose. Acta Derm. Venereol., 2019, 99(6), 620-621.
[http://dx.doi.org/10.2340/00015555-3148] [PMID: 30734049]
[34]
Walsh, D.A.; Hu, D.E.; Mapp, P.I.; Polak, J.M.; Blake, D.R.; Fan, T.P. Innervation and neurokinin receptors during angiogenesis in the rat sponge granuloma. Histochem. J., 1996, 28(11), 759-769.
[http://dx.doi.org/10.1007/BF02272149] [PMID: 8968728]
[35]
Guha, S.; Eibl, G.; Kisfalvi, K.; Fan, R.S.; Burdick, M.; Reber, H.; Hines, O.J.; Strieter, R.; Rozengurt, E. Broad-spectrum G protein-coupled receptor antagonist, [D-Arg1,D-Trp5,7,9,Leu11]SP: A dual inhibitor of growth and angiogenesis in pancreatic cancer. Cancer Res., 2005, 65(7), 2738-2745.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3197] [PMID: 15805273]
[36]
Sporn, M.B. The war on cancer. Lancet, 1996, 347(9012), 1377-1381.
[http://dx.doi.org/10.1016/S0140-6736(96)91015-6] [PMID: 8637346]
[37]
Fackler, O.T.; Grosse, R. Cell motility through plasma membrane blebbing. J. Cell Biol., 2008, 181(6), 879-884.
[http://dx.doi.org/10.1083/jcb.200802081] [PMID: 18541702]
[38]
Jacob, A.; Prekeris, R. The regulation of MMP targeting to invadopodia during cancer metastasis. Front. Cell Dev. Biol., 2015, 3, 4.
[http://dx.doi.org/10.3389/fcell.2015.00004] [PMID: 25699257]
[39]
Murphy, D.A.; Courtneidge, S.A. The ‘ins’ and ‘outs’ of podosomes and invadopodia: Characteristics, formation and function. Nat. Rev. Mol. Cell Biol., 2011, 12(7), 413-426.
[http://dx.doi.org/10.1038/nrm3141] [PMID: 21697900]
[40]
Ma, J.; Yuan, S.; Cheng, J.; Kang, S.; Zhao, W.; Zhang, J. Substance P promotes the progression of endometrial adenocarcinoma. Int. J. Gynecol. Cancer, 2016, 26(5), 845-850.
[http://dx.doi.org/10.1097/IGC.0000000000000683] [PMID: 27051050]
[41]
Mehner, C.; Hockla, A.; Miller, E.; Ran, S.; Radisky, D.C.; Radisky, E.S. Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget, 2014, 5(9), 2736-2749.
[http://dx.doi.org/10.18632/oncotarget.1932] [PMID: 24811362]
[42]
Lee, M.; McCloskey, M.; Staples, S. Prolonged use of aprepitant in metastatic breast cancer and a reduction in CA153 tumour marker levels., Int. J. Cancer Clin. Res., 2016, 3, 071.
[http://dx.doi.org/10.23937/2378-3419/3/6/1071]
[43]
Warburg, O. On the origin of cancer cells. Science, 1956, 123(3191), 309-314.
[http://dx.doi.org/10.1126/science.123.3191.309] [PMID: 13298683]
[44]
Medrano, S.; Gruenstein, E.; Dimlich, R.V. Substance P receptors on human astrocytoma cells are linked to glycogen breakdown. Neurosci. Lett., 1994, 167(1-2), 14-18.
[http://dx.doi.org/10.1016/0304-3940(94)91017-0] [PMID: 7513838]
[45]
Basu, S.; Chen, W.; Tchou, J.; Mavi, A.; Cermik, T.; Czerniecki, B.; Schnall, M.; Alavi, A. Comparison of triple-negative and estrogen receptor-positive/progesterone receptor-positive/HER2-negative breast carcinoma using quantitative fluorine-18 fluorodeoxyglucose/positron emission tomography imaging parameters: A potentially useful method for disease characterization. Cancer, 2008, 112(5), 995-1000.
[http://dx.doi.org/10.1002/cncr.23226] [PMID: 18098228]
[46]
Schütz, F.; Stefanovic, S.; Mayer, L.; von Au, A.; Domschke, C.; Sohn, C. PD-1/PD-L1 pathway in breast cancer. Oncol. Res. Treat., 2017, 40(5), 294-297.
[http://dx.doi.org/10.1159/000464353] [PMID: 28346916]
[47]
Tebas, P.; Spitsin, S.; Barrett, J.S.; Tuluc, F.; Elci, O.; Korelitz, J.J.; Wagner, W.; Winters, A.; Kim, D.; Catalano, R.; Evans, D.L.; Douglas, S.D. Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: Phase 1B trial of aprepitant in HIV-1-infected adults. AIDS, 2015, 29(8), 931-939.
[http://dx.doi.org/10.1097/QAD.0000000000000638] [PMID: 25915168]
[48]
Beckers, R.K.; Selinger, C.I.; Vilain, R.; Madore, J.; Wilmott, J.S.; Harvey, K.; Holliday, A.; Cooper, C.L.; Robbins, E.; Gillett, D.; Kennedy, C.W.; Gluch, L.; Carmalt, H.; Mak, C.; Warrier, S.; Gee, H.E.; Chan, C.; McLean, A.; Walker, E.; McNeil, C.M.; Beith, J.M.; Swarbrick, A.; Scolyer, R.A.; O’Toole, S.A. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology, 2016, 69(1), 25-34.
[http://dx.doi.org/10.1111/his.12904] [PMID: 26588661]
[49]
Liang, J.; Hänsch, G.M.; Hübner, K.; Samstag, Y. Sulforaphane as anticancer agent: A double-edged sword? Tricky balance between effects on tumor cells and immune cells. Adv. Biol. Regul., 2019, 71, 79-87.
[http://dx.doi.org/10.1016/j.jbior.2018.11.006] [PMID: 30528536]
[50]
Robinson, P.; Kasembeli, M.; Bharadwaj, U.; Engineer, N.; Eckols, K.T.; Tweardy, D.J. Substance P receptor signaling mediates doxorubicin-induced cardiomyocyte apoptosis and triple-negative breast cancer chemoresistance. BioMed Res. Int., 2016. 20161959270
[http://dx.doi.org/10.1155/2016/1959270] [PMID: 26981525]
[51]
Faber, A.C.; Wong, K.K.; Engelman, J.A. Differences underlying EGFR and HER2 oncogene addiction. Cell Cycle, 2010, 9(5), 851-852.
[http://dx.doi.org/10.4161/cc.9.5.11096] [PMID: 20160489]
[52]
Mayordomo, C.; García-Recio, S.; Ametller, E.; Fernández-Nogueira, P.; Pastor-Arroyo, E.M.; Vinyals, L.; Casas, I.; Gascón, P.; Almendro, V. Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2. J. Cell. Physiol., 2012, 227(4), 1358-1366.
[http://dx.doi.org/10.1002/jcp.22848] [PMID: 21604273]
[53]
Alfieri, A.B.; Cubeddu, L.X. Efectos de los antagonistas de los receptores NK1 y de la dexametasona sobre la inflamación neurogénica inducida por ciclofosfamida y por radiación X, en la rata. AVFT, 2004, 23, 61-66.
[54]
Alfieri, A.B.; Cubeddu, L.X. Role of NK1 receptors on cisplatin-induced nephrotoxicity in the rat. Naunyn Schmiedebergs Arch. Pharmacol., 2000, 361(3), 334-338.
[http://dx.doi.org/10.1007/s002109900196] [PMID: 10731048]
[55]
Kitchens, C.A.; McDonald, P.R.; Pollack, I.F.; Wipf, P.; Lazo, J.S. Synergy between microtubule destabilizing agents and neurokinin 1 receptor antagonists identified by an siRNA synthetic lethal screen. FASEB J., 2009, 23, 756.
[56]
Muñoz, M.; Coveñas, R. Safety of neurokinin-1 receptor antagonists. Expert Opin. Drug Saf., 2013, 12(5), 673-685.
[http://dx.doi.org/10.1517/14740338.2013.804059] [PMID: 23706125]
[57]
Muñoz, M.; Rosso, M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest. New Drugs, 2010, 28(2), 187-193.
[http://dx.doi.org/10.1007/s10637-009-9218-8] [PMID: 19148578]
[58]
Molinos-Quintana, A.; Trujillo-Hacha, P.; Piruat, J.I.; Bejarano-García, J.A.; García-Guerrero, E.; Pérez-Simón, J.A.; Muñoz, M. Human acute myeloid leukemia cells express Neurokinin-1 receptor, which is involved in the antileukemic effect of Neurokinin-1 receptor antagonists. Invest. New Drugs, 2019, 37(1), 17-26.
[http://dx.doi.org/10.1007/s10637-018-0607-8] [PMID: 29721755]
[59]
Kramer, M.S.; Cutler, N.; Feighner, J.; Shrivastava, R.; Carman, J.; Sramek, J.J.; Reines, S.A.; Liu, G.; Snavely, D.; Wyatt-Knowles, E.; Hale, J.J.; Mills, S.G.; MacCoss, M.; Swain, C.J.; Harrison, T.; Hill, R.G.; Hefti, F.; Scolnick, E.M.; Cascieri, M.A.; Chicchi, G.G.; Sadowski, S.; Williams, A.R.; Hewson, L.; Smith, D.; Carlson, E.J.; Hargreaves, R.J.; Rupniak, N.M. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science, 1998, 281(5383), 1640-1645.
[http://dx.doi.org/10.1126/science.281.5383.1640] [PMID: 9733503]
[60]
Muñoz, M.; Crespo, J.C.; Crespo, J.P.; Coveñas, R. Neurokinin-1 receptor antagonist aprepitant and radiotherapy, a successful combination therapy in a patient with lung cancer: A case report. Mol. Clin. Oncol., 2019, 11(1), 50-54.
[PMID: 31289677]

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